The Usage of Heart Failure Biomarkers in China

Xinli Li, MD, PhD and Iokfai Cheang, MBBS

1Department of Cardiology, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China

Current Status of Heart Failure

Heart failure (HF) is a set of complicated clinical syndromes, in consequence of impaired ventricular filling or eject function which caused by any structural or functional abnormality. The main manifestations of HF are dyspnea, limited activity tolerance, edema and fluid retention. Being the final stage of various severe diseases, the high morbidity and mortality rate of HF makes it one of the most studied cardiovascular diseases.

Coronary artery disease, hypertension, diabetes mellitus, are among the many diseases that can be related to aging, on the other hand it can also lead to the development of heart failure [1]. As the result of extending human lifespans, heart failure has become a distinctly challenging problem [2].

The Asia-Pacific region compared to the Western regions has a younger mean age [3] and a relatively higher risk of cardiovascular death [4]. More specifically in China, due to economic improvement, dietary change, and also the extending of human lifespans, all these factors have profoundly increased the risk of CAD, HTN and DM. which are known to contribute to a higher mortality and morbidity in HF [5]. These problems urge us to take more attention and efforts to learn and to provide solutions.

Heart failure may develop slowly over time and also may strike abruptly. When HF occurs, as the result of the slow and progressive damage to the heart muscle, it eventually causes the muscle to remodel and lead to irreversible hemodynamic problems. This also makes the diagnosis of heart failure highly difficult.

The Diagnosis of Heart Failure

Over decades, scientists and medical professionals have been trying to understand the mechanism of HF and how to cure it. Substantial studies have led to the etiology and mechanisms of HF becoming clear. Treatment options which can help to control the progress of HF have been improved over time. Biomarkers came to light and became a useful tool to help us diagnosis and evaluate the severity of HF.

On the other hand, we have learnt that in preheart failure stage, HF could be prevented. On the contrary, the later stages of HF are unlikely to be reversed. Therefore, early assessment criteria are essential in the treatment guidelines of HF [6].

According to the guidelines in China [7] and Europe [8], various biological markers are recommended regarding diagnosis and treatment assessment. In the following, we reviewed some of these studies to look into the use of the biomarkers in China.

The Present and the Past of HF Biomarkers in China

In the last decades, we have learnt that HF patients often suffer anemia at the same time. We have learnt the patients could develop kidney malfunction and cardio-renal syndrome. We look into the internal environment to explore all the possibilities.We extensively used different indexes and tried to predict HF., We evolved through studies and experiences. From theory to practice, we have discovered that, every single cell inside our body has its own way to deal with the disruption caused by HF.But when do the changes occur? When HF breaks the balance inside our body, there are tremendous‘ metabolic storms’ which make it even harder to analyze the lead. A large number of molecules appear and chains of chemical reaction start. Thus,we trace these threads and study their progress and development over time. We look into every detail and find out which of them is primary, so the vision inside this ‘storm’ can become clearer.

After all the studies, these biomarkers have proven to be a helpful tool in treating HF among different populations. Thus, HF markers are widely spread and used in China and all over the world. Regarding putting it into actual use, to answer those questions and clear out all the confusion, there are three major criteria a biomarker must fulfill to be clinically useful. First, accurate and repeated measurements must be available to the clinician at a reasonable cost and with short turnaround times; second, the biomarker must provide information that is not already available from a careful clinical assessment; finally,knowing the measured level should aid in medical decision-making [9]. In addition, as regards the different sources and origins of the markers, they can be loosely categorized into: (1) Comorbidities;(2) Neurohormonal activation; (3) Remodeling; (4)Myocardial stress / injury [10]; which have slight distinctions on various individuals and may not fulfill the above criteria.

This indicates that the efficacy could be different in different races. In the following, we will focus on the research done in China and look in to the active biomarkers in use, to see the usage and the values of HF markers.

Common Biomarkers in Clinical Practice

C-Reactive Protein (CRP) and High- sensitivity CRP (Hs-CRP)

In flammation plays a critical part in the pathogenesis and progression of many forms of heart failure. Therefore the biomarkers of in fl ammation have become much studied and in which the measurements of CRP appear to be useful. But in the actual use, the increase of CRP level can be seen in a number of diseases, such as infections, TIA,cerebral infarction, asthma, SLE, diabetes, etc.which affect the accuracy of CRP [11]. However,CRP and hs-CRP are still commonly used as HF markers in China, especially in the non- fi rst tier cities, often because of its convenience. And it is also because to exclude the in fl ammation and the other infections, using hs-CRP can provide the indirect evidence to help physicians and patients to prevent cardiovascular disease and to predict the prognosis [12].

Brain-Type Natriuretic Peptide (BNP)and N-Terminal Prohormone of BNP(NT- proBNP)

Myocardial necrosis and oxidative stress are the major sources of BNP and NT-pro/BNP. The increased stress of myocardial cells, myocardial isocheimal injury and remodeling of myocardial cells, can significantly increase the secretion of NT-proBNP [13], and therefore helps evaluate the severity of acute heart failure and prognosis. Due to their different half-life period, the ratio can assist diagnosis and reflect on the course of disease.

They are considered the benchmark when other biomarkers are compared. Although there is a lack of retrospective research of the usage rate of BNP/NT-proBNP in China, they are widely used in the diagnosis of cardiovascular disease since they had been included in the 2007 guidelines [14]. Due to the relatively high sensitivity and specificity, BNP/NT-proBNP also appears to be the first choice biomarker in HF guidelines all over the world [7,8]. Despite the fact that BNP and NT-proBNP are proven to have an essential value of diagnosis, risk stratification, efficacy assessment, prognosis and management in both acute and chronic heart failure,the usages are affected by factors such as age, sex,renal function and other factors.

Research Progress

Besides the markers above, new biomarkers have been added to the guidelines. Soluble ST-2 (sST-2) and Galectin-3 (Gal-3) seem to be distinctively helpful in diagnosis.

Thomas et al. detected the biological markers of heart failure and found some specific expression of markers [15]: SERPINA3 (Serpin peptidase inhibitor, clade A member 3), VSIG4 (V-set and immunoglobulin domainecontaining 4 protein), etc.These provide new ideas and clues for the serologyspecific examination. More studies are needed to discuss their effectiveness and feasibility for the dignostic process.

Soluble ST-2 (sST-2)

sST-2 is secreted when myocardial cells and myocardial fibroblasts are in stress. As sST-2 in a lower or normal level, the other form of ST-2, ST2L, can combine with their common ligand IL-33 to protect the heart; on the contrary, an increased level of sST-2 would competitive bind with IL-33, less ST2L can combine with IL-33 which suppresses the protective function of IL-33. sST-2 is a new biomarker associated with the severity of HF and can be used as a new indicator, having 61.10% sensitivity and 82.10% specificity in predicting a poor short term prognosis [16]. And there can also predict the mortality of HF and cardiovascular disease for elderly [17].

Galectin-3 (Gal-3)

Gal-3 as an in fl ammation factor can promote the migration of macrophage cells, fibroblast proliferation and collagen formation. All of the above are major elements of myocardial remodeling. In the process of ongoing HF caused by remodeling, the heart produces Gal-3 and releases it into peripheral blood [18]. As a result, Gal-3 can provide a clear view for us to evaluate the late stage chronic HF patients and even a greater specificity in predicting the severity in HF [19].

Usage of Those Biomarkers

Stopping and slowing down the ventricular remodeling has been the subject of much recent research.And has become the main direction of clinical treatment of heart failure. All these biomarkers give us a clear look into the status of HF and provide us effective screening and early diagnosis options.

The benchmarked HF biomarker BNP and NT-proBNP are still the most common HF markers used in China. In various medical studies, they have been used as an indicator of the efficacy of HF markers [20].

In heart failure patients, the elevated level of NT-proBNP and hs-CRP are synchronized and either two are increased along with grading of NYHA HF scale. At the same time with the use of hs-CRP, the physician would have a better view and reliable index in the diagnosis, and can make more effective treatment plans and evaluate the prognosis of heart failure [21].

More recent biomarkers specialize in different physiological pathways such as myocardial injury,in flammation, and remodeling which are crucial at risk strati fication of heart failure. For example,sST-2 and Gal-3 have a close connection to the HF patients’ short-term mortality [22]. Additionally, it indicates sST-2 and Gal-3 can directly re flect the pathological change inside the body and capture the information that the older biomarkers cannot provide.

Although research shows that sST-2 can increase in multiple other diseases and lack of specificity,they are proven to be useful in combination with other markers. A study we have done shows [18],with NT-proBNP or Troponin-T hs CalSet (cTnT-hs), sST-2 is a better method to assess patients’prognosis. In severe cases of heart failure, sST-2 is an independent predictor for the mortality within a year. Similar to that, using Gal-3 has its own advantages and disadvantages. Gal-3 takes advantage on assessing the therapeutic effect that also might indicate a whole new treatment approach to HF and perhaps even other diseases present in increased level s of Gal-3 [19].

Future Expectations

To accurately predict the risk of heart failure without delay using limited information and/or risk factors is the prime goal in treating heart failure. For the present we still lack a method that can achieve all these requirements. Biomarkers are now widely used in clinical practice. These familiar items that were in use all have them own features, but none of them can directly indicate the early happening of HF. The truth is, heart failure biomarkers have much more progress to be made. New biomarkers and new pathways have a long process of development. Some of the biological processes and half-life of these new markers within the human body are still unclear. With continuous effort,potential discoveries could bring about improvements in diagnosis, evaluation or treatment in a new dimension.

Also, all those different measurements and indexes we have used in other methodologies could now have a brand new usage on HF, such as red cell distribution width (RDW) [23], D-dimer [24],Endothelin-1 (ET-1), Cystatin C (CysC) [25], TNF-α, etc. As well as the routine laboratory result –serum sodium level or other circulating metabolites are also potentially helpful tools in the HF chemical storm. In a recent retrospective study we have done in patients with acute heart failure, with NT-proBNP,sST2 and serum sodium, could potentially predict 1-year mortality [26]. What is more, hypothermia seems to be an independent predictor of short and intermediate term mortality in acute heart failure[27]. These markers and all the physical findings would be beneficial for both the patients and the health care providers in thousands of the primary health care facilities, when the ‘perfect’ biomarkers are not yet available.

Individualized Diagnosis and Treatment

For the diagnosis and assessment with the common biomarkers such as BNP, individuals could present with various manifestations depending on the different mechanism of heart failure. Therefore, it can be classified based on the ejection fraction in to heart failure with reduced ejection fraction (HFrEF)and heart failure with preserved ejection fraction(HFpEF). BNP and NT-proBNP are elevated in both HFpEF and HFrEF, but they tend to be higher in HFrEF than HFpEF [28].

Heart failure with mid-range ejection fraction(HFmrEF) is added into the 2016 ESC Guidelines[8]. As the pathophysiology of heart failure involves in flammation, oxidative stress, neurohormonal disorders and cardiac and matrix remodeling and other aspects, all of these aspects have their corresponding biomarkers. In the future,with the proper classification and analysis of the new biomarkers, individualized assessment can be established. More research is required to evaluate the relationship between the markers and their Individualized use.

Combination Use of the Heart Failure Markers

In the present stage, it is clear that using a single indicator is not an effective approach to the assessment of HF. The complexity and diversity of HF etiology make it difficult to guarantee accuracy. To get a better view for patients’ heart failure condition, the combination use of biomarkers is undoubtedly a wise application in clinical use. Research has shown with multiple markers in use, the accuracy could be improved [21, 23, 25].

However it is rather unrealistic for patients to take all the examinations at once. To fulfill effective clinical use, even with the simplest index,serum sodium level can provide an improvement in assessing prognosis. Combination uses of the proper markers are a wise move to fulfill an effective clinical use.

Therefore, besides finding the ‘perfect’ biomarkers in use, looking back and uniting the new and existing knowledge, eventually to find out the most comprehensive and effective diagnostic method for HF should be the priority now.

Con fl ict of Interest

The authors declare no con flict of interest.

REFERENCES

1. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham Study.Am J Cardiol 1974;34(1):29–34.

2. Chen S, Li X. Research progress in diabetes mellitus and heart failure.Chin J Multiple Org Dis Elderly 2012;11:641–4.

3. Kristensen SL, Martinez F, Jhund PS, Arango JL, Be˘lohlávek J,McMurray JJ, et al. Geographic variations in the paradigm-HF heart failure trial. Eur Heart J 2016;37(41):3167–74.

4. Metra M, Mentz RJ, Armstrong PW, Clausell N, Corbalan R,Costanzo MR. Geographic differences in patients in a global acute heart failure clinical trial (from the ASCEND-HF trial). Am J Cardiol 2016;117(11):1771–8.

5. Zhang J, Zhang Y. On behalf of China heart failure registry. China Heart Failure Registry Study - a multicenter, prospective investigation for preliminary analysis on etiology, clinical features and treatment in heart failure patients. Chin Circ J 2015;30:413–6.

6. Li X. The importance of prevention and early intervention for heart failure. Chin J Heart Heart Rhythm(Electron Ed) 2015;3(02):80.

7. Chinese Society of Cardiology of Chinese Medical Association. 2014 Chinese guidelines for the diagnosis and treatment of heart failure. Chin J Cardiol 2014;42(02):98–122.

8. The Task Force for the diagnosis and treatment of acute and chronic heart failure of the ESC. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur J Heart Fail 2016;18(8):891–975.

9. Morrow DA, de-Lemos JA.Benchmarks for the assessment of novel cardiovascular biomarkers.Circulation 2007;115:949–52.

10. Gaggin HK, Januzzi Jr JL. Cardiac biomarkers and heart failure. Am Coll Cardiol 2015 [cited 2016 Oct 15]. Available online at: http://www.acc.org/latest-in-cardiology/articles/2015/02/09/13/00/cardiacbiomarkers-and-heart-failure.

11. Zhang X, Li G, Zhang Z. Clinical significances of C - reactive protein and hypersensitive C - reactive protein. Chin J Allergy Clin Immunol 2011:05:74–9.

12. Jin Y, Qiu G, Zhang S. Expression characteristic of serum high-sensitivity C - reactive protein in cardiovascular lesions. Chin J Lab Med 2002;25:357–9.

13. Emdin M, Vittorini S, Passino C. Old and new biomarkers of heart failure.Eur J Heart Fail 2009;11:331–5.

14. Chinese Society of Cardiology of Chinese Medical Association.2007 Chinese Guidelines for the Diagnosis and Treatment of Heart Failure. Chin J Cardiol 2007;35(12):1076–95.

15. di Salvo TG, Yang KC, Brittain E,Abs T, Maltais S, Hemnes A. Right ventricular myocardial biomarkers in human heart failure. J Card Fail 2015;21(5):398–411.

16. Zhang X, Gao R, Xu X, Wang K,Jin M, Li X, et al. Value of serum sST-2 in evaluating severity and short-term prognosis of patients with heart failure. Jiangsu Med J 2016;42:645–7.

17. Parikh RH, Seliger SL, Christenson R, Gottdiener JS, Psaty BM,deFilippi CR. Soluble ST2 for prediction of heart failure and cardiovascular death in an elderly,community-dwelling population. J Am Heart Assoc 2016;5:e003188.

18. Jin M, Wai S, Li R, Li X. The research development of galectin-3 in cardiac remodeling for heart failure. J Clin Cardiol (China)2016;32:441–5.

19. Li S, Li R, Zhang H, Jin M, Wang K,Li X, et al. Value of sST2 and galectin-3 in predicting short-term prognosis of patients with acute heart failure.Jiangsu Med J 2016;42:402–4.

20. Li X, Zhang J, Huang J, Ma A,Yang J, Li W, et al. A multicenter,randomized, double-blind, parallelgroup, placebo-controlled study of the effects of Qili Qiangxin capsules in patients with chronic heart failure. J Am Coll Cardiol 2013;62(12):1065–72.

21. Niu F, Liu W, Dou J. Investigation about the relativity between N-terminal pro-brain natriuretic peptide and high sensitive C-reactive protein in patients with heart failure. J Med Theor Pract 2013;26:143–4.

22. Xu X, Jia R, Wang T, Liu Q, Zhen Z. Correlation study of galectin-3 and soluble ST2 levels in heart failure diagnosis. Chin Circ J 2016;31:866–9.

23. Xu K, Lin L, Lin J, Zheng J, Cai D.Relationship between red cell distribution width and complication risk in patients with acute myocardial infarction. Chin J Arterioscler 2010;18:569–73.

24. Zhang J, Gao R, Li X, Wang H.Clinic significance of D-dimer in short-term prognosis of patients with acute heart failure.J Shanghai Univ (Nat Sci Ed)2016;22:376–80.

25. Hao Y, Hua J, Wang Y, Zhang J,Ma ZC. In fl uence of rh-BNP on plasma Gal-3, ET-1, CysC levels and cardiac function in patients with acute heart failure. J Clin Emerg(China) 2016;17:462–5.

26. Jin M, Wei S, Gao R, Wang K, Xu X,Li X, et al. Predictors of long-term mortality in patients with acute heart failure. Int Heart J 2017;3(58) (in press). DOI: http://doi.org/10.1536/ihj.16-219.

27. Omar HR, Guglin M. Hypothermia is an independent predictor of short and intermediate term mortality in acute systolic heart failure: insights from the ESCAPE trial. Int J Cardiol 2016;220:729–33.

28. Maisel AS, McCord J, Nowak RM,Hollander JE, Wu AH, Duc P, et al. Bedside B-type natriuretic peptide in the emergency diagnosis of heart failure with reduced or preserved ejection fraction. Results from the Breathing Not Properly Multinational Study. J Am Coll Cardiol 2003;41(11):2010–7.